Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group

The International Working Group (IWG) on Immune Thrombocytopenia (ITP) recently described new terminology, uniform definitions, and outcome criteria for the diagnosis and management of ITP in children and adults.¹  These proposals were adopted in recent guidelines and consensus reports and are in widespread use.^2,3  ITP was defined as “severe” when the presence or recurrence of bleeding manifestations was sufficient to mandate treatment, regardless of the platelet count. Use of terms such as “mild” or “moderate” ITP was discouraged because of their vagueness. The IWG recommendations for evaluating the effectiveness of treatments are based on the platelet count as an objective surrogate, although the group acknowledged that a platelet count threshold is inadequate as the sole parameter for making such decisions. The reason underlying this choice was the lack of standardized bleeding and quality of life (QoL) assessment tools for ITP. The IWG noted that none of the few bleeding assessment tools available in the literature could be easily adopted and/or were validated for ITP. Therefore, any further investigation focusing on bleeding events and their relationship with platelet counts or other individual attributes would be fraught with difficulties.

This article describes an ITP-specific Bleeding Assessment Tool (ITP-BAT), version 1.0, based on a more precise definition of bleeding manifestations and on the grading of their severity. A standardized data collection form has also been developed to facilitate collection of information and communication among physicians and investigators.

The IWG on ITP holds annual conferences during the American Society of Hematology (ASH) and European Hematology Association (EHA) meetings. In 2008, the group agreed that standardization of bleeding assessment should receive priority. During the 2010 ASH meeting in Orlando, Florida, a first half-day conference was formally convened. After a focused review of the available literature, the IWG concluded that because of the lack of robust evidence to support any specific existing scale, a consensus-based approach was preferable. The widely used World Health Organization (WHO) scale⁴  (and its many variations), which has often been adopted in recent clinical trials, was designed to grade bleeding in patients with chemotherapy-induced thrombocytopenias, but it has limited sensitivity and accuracy when it comes to accurately describing the bleeding phenotype of ITP patients. It is prone to excessive subjective interpretations and uses broad and overlapping categories of unequal clinical intervals. Impact of bleeding at single sites vs global impact is not measurable with this scale.⁵  It was also concluded that none of the BATs devoted to congenital hemostatic disorders^6,7  was entirely suitable for ITP. Three other IWG meetings on this topic were convened during the EHA 2011 and 2012 meetings in London (United Kingdom) and Amsterdam (The Netherlands) and the ASH 2011 meeting in San Diego (California).

The IWG concluded that a single BAT should be produced for use in both children and adults with ITP. It should be easily adapted to the different phases of the disease and amenable for use in clinical trials. The ITP-BAT should have a construction compatible with the clinical aspects of the disease in terms of content and face validity, avoid ambiguous definitions and terminology, and be usable in both clinical and research contexts. In addition, the grading of severity of each bleeding manifestation should encompass few points, so that reproducibility among investigators would be enhanced. The panel therefore agreed that a standardized data collection form would be useful to maintain consistency in reporting and for comparative studies. The ITP-BAT should be useful for defining bleeding events and making correlations with QoL measures, for other bleeding determinants, for risk factors and platelet counts, and among different patients or for the same patient over the course of the disease and its different treatments. A subcommittee was assigned the duty of preparing a preliminary draft of the manuscript and supplemental material based on the progressive consensus reached among the members during face-to-face conferences and several rounds of Delphi-like questionnaires. A draft of the manuscript was approved at a conference held during the 2012 EHA meeting. Changes were subsequently implemented with the approval of all authors. Three external experts provided further review of the manuscript to ensure that the proposal was intrinsically logical, consistent, clear, and applicable to ITP. None of IWG members and external reviewers received honoraria or travel support. More detailed information is available in supplemental Appendix 1, Methodology.

An analysis of the literature was carried out by M.R. and R.S. Articles relevant to the evaluation of bleeding manifestations in ITP were identified among those listed in the systematic literature review carried out by Ruggeri et al,⁸  which initially included publications available up to 2006. Articles published subsequently, up to the end of 2011, were identified by using the same criteria. Articles that reported on bleeding assessment in patients with thrombocytopenia secondary to chemotherapy were also considered. For more detailed information, see supplemental Appendix 1, Methodology. Some examples of bleeding scales are shown in supplemental Appendix 2.

One of the main aims of the proposal is to provide a terminology for hemorrhagic manifestations in ITP that integrates and is consistent with the terminology already adopted for other bleeding disorders and that is relevant for the purpose of developing an ITP-specific bleeding assessment. The IWG recognized that standard medical textbooks differ in the terms they use to describe bleeding manifestations, particularly for skin and visible mucosae, and that adherence to single definitions is limited.

Because platelets are essential for primary hemostasis, bleeding in ITP results most commonly from failure to prevent leakage of blood from small blood vessels. The most frequent hemorrhagic manifestation in ITP is purpura. Purpura broadly encompasses any kind of mucocutaneous bleeding; it is commonly referred to as “dry” when bleeding is confined to the skin and “wet” when mucous membranes are also involved. The IWG recommends against the use of these terminologies because they lack precision. A more precise definition of bleeding symptoms affecting the skin and visible mucous membranes is given in Table 1, and we recommend that reporting complies with this set of definitions. For other bleeding manifestations (eg, melena, gastrointestinal bleeding, hematuria), standard definitions should be adopted. A complete list of bleeding manifestations is available in supplemental Appendix 3, along with explanatory definitions and their relevance to ITP.

Bleeding symptoms are grouped into three major domains: skin (S), visible mucosae (M), and organ (and internal mucosae) (O), as shown in Table 2. The table also defines the grades of severity of the various types of bleeding in each domain and is harmonized with a data collection form suitable for database processing, which is available in supplemental Appendix 4. The data collection form is a guide to fill in the classification and grading in Table 2. Although it can be skipped by examiners familiar with this tool, it could be useful for implementing an electronic version of the ITP-BAT and for subsequent database processing.

The bleeding grade should be assigned by a physician or trained nurse at presentation and at each follow-up visit. For each type of bleeding, only the worst incident bleeding manifestation occurring during the interval since the previous evaluation should be recorded. Grading ranges from 0 to 4 for epistaxis and for bleeding in the organ domain, except ocular and intracranial bleeding (grade 0 and 2 to 4). For the remaining bleeding sites (in skin and mucosal domains) four grades (0 to 3) were deemed sufficient. Grade 5 is assigned to any fatal bleeding. The IWG recommends providing a short description of any fatal bleeding. By taking the highest grade for each domain, the SMO Grade (SMOG) index is obtained. For example, if during the period under evaluation, the highest grade is 2 for the skin domain, 2 for the mucosal domain, and 0 for the organ domain, the index is S2M2O0. A major effort was made by the IWG to ensure that the different bleeding manifestations are graded consistently from the least to the most severe and that, within the same domain, an identical grade corresponds to a similar clinical impact. This consensus was based on the clinical judgment of the IWG members. For example, to receive a grade >1, all non-open skin and non-open mucosal bleeding (petechiae, ecchymoses, subcutaneous hematomas, subconjunctival hemorrhages) should be visible and assessable at the time of visit. In fact, the IWG decided that for these types of bleeding, patient self-assessment or assessment by the patient’s general practitioner would not have sufficient accuracy and reproducibility to be reliable. Furthermore, these manifestations may remain visible for days or even weeks and be easily captured at scheduled follow up visits, even if the patient is not seen when they arise. Medical records based on direct observation by the attending physician should be included for open-skin and open-mucosal bleeding (minor skin wounds, epistaxis, gum, bleeding from bites to lips and tongue or after loss/extraction of deciduous teeth) and all organ bleeding. Such medical records are acceptable for assigning a grade 3 to open-skin and open-mucosal bleeding. For bleeding in the organ domain and internal mucosae, medical reports are of critical importance and should be considered for grading, as detailed in Table 2.

For particular bleeding manifestations, objective diagnosis is mandatory, as specified in Table 2. It is critical to consider all bleeding that occurred in the interval period, including that ongoing at the time of the visit. Residual findings of previously reported bleeding (eg, petechiae or ecchymoses appearing blue or yellowish green and not red) should be excluded from the assessment.

The IWG recommends against summing up the worst manifestations in all domains to obtain a total sum score instead of generating a SMOG index (separately reporting each of the 3 scores). The total sum score will provide little clinical relevance. For example, it is self-evident that organ bleeding usually trumps bleeding manifestations in all the remaining domains. So, for example, a total sum score of 4 produced by a combination of domain grades, such as S1M1O2, is certainly of more descriptive and of major clinical relevance when compared with a total sum score of 4 that may be derived from a different combination of domain grades, such as S2M2O0, in which there is no organ bleeding.

For particular purposes, provided that the different domains are always treated separately, other modalities of reporting are possible with the SMOG system. For instance, all worst manifestations for each (or selected) bleeding listed in Table 2 could be recorded and graded (eg, petechiae 2, ecchymosis 1, mouth bleeding 1, epistaxis 2, and heavy menses 2). This approach might be useful for very detailed analyses (eg, to evaluate the relationship of particular bleeding manifestations with some determinants of the disease, such as platelet count, or to assess the impact on QoL or in particular for a clinical trial). The value of summing up all worst grades for all manifestations within each domain remains of uncertain utility and of ambiguous interpretation, and the IWG discourages this form of analysis. Despite its overall rarity, considering the lifelong potential functional impairment caused by intracranial bleeding, the IWG recommends that all intracranial bleedings be reported, irrespective of their grade. For example, if a woman had S2 (subcutaneous hematoma) M2 (epistaxis) O3 (menorrhagia) and an intracranial bleeding grade 2 (post trauma, requiring hospitalization), the SMOG index is S2M2O3 (intracranial 2). If the same patient also had intracranial bleeding grade 3, the SMOG index is S2M2O3 (intracranial 3).

Averaging the grades in each domain over repeated visits in a defined period or phase of the disease could be used to evaluate improvement or worsening of the bleeding severity, either in individual patients or in a cohort of subjects.

The grading scale, the electronic version of the data collection forms, and a series of illustrative pictures taken from patients with ITP or other causes of thrombocytopenia are available on the website of the Hematology Project Foundation (http://itpbat.fondazioneematologia.it/).

The IWG also proposed a provisional grading to assess the severity of bleeding after hemostatic challenges or surgery (Table 3). This scale could be useful for guiding the description of bleeding to identify a minimal platelet threshold that provides hemostasis for a specific procedure. Table 3 is not part of the SMOG.

A pilot study on 50 ITP patients from 5 different centers was conducted to assess the feasibility of the SMOG, the readability and lack of ambiguities and inaccuracies in the data collection forms, and the understanding and applicability of the grading scale. Concordance between two observers (an expert physician and a trained nurse or a young investigator) who investigated the same patient separately, was evaluated in 40 cases. The time needed to complete the questionnaire ranged from 5 to 20 minutes (<15 minutes in 45 of 50 cases, without considering dressing and undressing and any objective investigation required for the assessment), depending on the type and multiplicity of bleeding manifestations. This time could be significantly shortened by examiners familiar with this tool who could skip the data collection form and use Table 2 directly. The rate of concordance among observers (two for each assessment) was 100% for SMOG grading and above 80% for the single items in the various domains.

In clinical studies or trials, the bleeding assessment should be always made at preestablished intervals, even if the patient was seen or received treatment before the end of the predetermined interval, to ensure consistent assessment. The IWG acknowledged that, as a consequence, the frequency of bleeding manifestations might be underestimated but concluded that registering all signs and symptoms irrespective of their grade was of limited utility and very demanding in practice. Moreover, by choosing a shorter interval between follow-up visits, the overall bleeding picture of the patient would be captured in terms of both severity and types of signs and symptoms. The interval between visits is left to the physician’s discretion and may vary depending on phase of disease, drug tested, patient’s needs, and purpose of recording. However, it is mandatory that in clinical trials, an identical between-visits interval is chosen for the investigational and comparator arm(s). The incidence rate of worst bleeding manifestations occurring during the observation period can be normalized to patient’s exposure time. As intervals between follow-up visits become shorter (eg, daily), this rate will approximate the true incidence of the signs and symptoms under investigation.

The IWG suggests that the follow-up schedule should reflect the different phases of the disease and be adjusted to capture any significant effect on bleeding due to change in the type of treatment or dose modification. A general suggestion is that the intervals between monitoring visits range from a week to a month, depending on the context and the aim of the trial. For cohort studies that investigate the natural history of the disease or the long-term efficacy of some treatments such as rituximab or splenectomy, longer intervals (eg, from 3 months to 1 year) may be acceptable.

In its previous report,¹  the IWG defined new criteria for assessing response to ITP treatments. These criteria were based on a minimal threshold platelet count and absence of bleeding. With the availability of the proposed ITP-BAT, a more precise definition of “absence of bleeding” can be provided. The IWG proposes that, for the purpose of response assessment, the single occurrence of grade 1 bleeding symptoms in the skin domain is not considered as “the presence of bleeding.” This decision was made to avoid consideration of minor symptoms, sometimes of uncertain significance or dubious relationship with ITP, which could lead to spuriously classifying patients as nonresponsive while not requiring treatment based on their platelet count.

The panel also agreed that regardless of the phase of the disease, the term “severe” ITP should be used only in patients who have “clinically relevant bleeding” and that the ability to maintain a platelet count sufficient to prevent “clinically significant bleeding” could be considered as response to treatment in refractory ITP. Clinically relevant or significant bleeding was defined by the presence of symptoms at presentation sufficient to mandate treatment or by the occurrence of new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increase in dose of current therapy. This operational definition can now be more precisely defined by using the proposed ITP-BAT. The IWG agreed that a bleeding manifestation can generally be labeled “severe or clinically relevant” if it is grade 3 for skin and/or grade 2 or higher for mucosal domains and/or higher than grade 1 for organ domain (S >2 and/or M >1 and/or O >1).

For the purpose of classification and potential comparison, all bleedings at least grade 3 for mucosal and organ domains (irrespective of the grade in the skin domain) can generally be considered to correspond to bleeding previously classified as grade 3 and 4 in the WHO scale. No other particular SMOG combination has been linked to descriptive terms such as “mild” or “moderate” ITP. In particular, any proposed SMOG combination for the purpose of prognostication or decision making should be validated by prospective studies.

Several BATs specific for ITP or other thrombocytopenias have been proposed,⁵  but so far none has gained sufficient popularity or consensus for widespread adoption (see supplemental Appendix 2). The most widely used scale dates back to 1981, stemming from a WHO initiative.⁴  It was produced as a recommendation for the standardization of reporting acute and subacute toxicity related to cancer treatment. Grading was based on clinical appreciation of the severity of bleeding manifestations. A recommendation was also made to avoid attaching any clinical significance to a particular grade (eg, debilitating and not life-threatening). In particular, hemorrhage was graded 0 (none), 1 (petechiae), 2 (mild blood loss), 3 (gross blood loss), 4 (debilitating blood loss). This scale was used in recent registration and extension studies with eltrombopag and, slightly modified to include fatal cases, in similar studies with romiplostim.^9-12  Although major bleeding in ITP, fortunately, is very infrequent, it is possible that the lack of sensitivity and standardization in bleeding assessment when these scales are used may have contributed to the failure of these studies to demonstrate a significant reduction in major bleeding compared with placebo.¹³ 

The IWG concluded that of the few scoring systems available in the literature, none can be adopted as a simple, reproducible, and clinically meaningful tool to describe the bleeding manifestations of ITP, and they unanimously decided that a new system based on the consensus of clinicians who are experts in adult and pediatric ITP should be proposed.

Two basic aspects characterize the proposed ITP-BAT: the enumeration and precise definition of the bleeding manifestations relevant to ITP (Tables 1 and 2) and the production of a scale to grade their severity (Table 2).

To overcome the intrinsically arbitrary nature of any system of grading, the IWG agreed that grading of bleeding severity should be grounded on the highest consensus within the panel when assigning identical clinical importance to a particular bleeding manifestation. Furthermore, skin bleeding, although of high personal impact is, in general, less dangerous than bleeding from mucosae, which may require blood transfusion, and organ bleeding is the most severe because it may potentially lead to major functional impairment or a life-threatening situation. The IWG concluded that these three anatomical domains should be considered separately (Table 2). For the sake of simplicity and consistency, the highest grade in each domain during the period of observation should be indicated in the SMOG index. However, as discussed above, alternative modalities of reporting are possible. The SMOG alphanumeric system can easily be adapted to an electronic database with an automatic calculation of grading and bleeding score from patients’ data collection forms. This system could also serve as a template for similar BATs to be used in other clinical situations characterized by thrombocytopenia.

The IWG recommends the adoption of the ITP-BAT v1.0 in future clinical studies investigating the effectiveness of old and new treatments. The ability of the SMOG format to describe bleeding manifestations in terms that are amenable to statistical analysis may also lend itself to investigations involving the natural course of the disease. To exemplify, the S, M, and O components could be adopted to investigate the correlation between bleeding manifestations and platelet counts, to the quality of life outcomes in prospectively evaluated cohorts, or to explore the impact of additional risk factors on the severity and type of bleeding.

In conclusion, this tool will require validation by appropriately designed, prospective clinical studies before widespread adoption in clinical practice. Further modifications of the ITP-BAT v1.0 are envisaged, based on the outcome of such studies and of other data reported. The recent finding that a simple scoring system based primarily on physical examination and grading of severity^14,15  (see also supplemental Appendix 2) showed a linear relationship between increased scores at presentation and subsequent failure to adequately respond to romiplostim¹⁴  suggests that additional prospective studies will help determine whether the proposed ITP-BAT can also be used in decision making or in prognostication.

This project was endorsed by the Scientific Working Group on Thrombocytopenias of the European Hematology Association and the Intercontinental Childhood ITP Study Group. Critical revision of the paper by three external reviewers—Paula Bolton-Maggs (UK), Beng Chong (Australia), and James George (USA)—was highly appreciated. The authors would also like to thank Donald Arnold (Canada), George Buchanan (USA), and Cindy Neunert (USA) for their critical suggestions. The authors also thank Claudia Guzzoni, an employee of Hematology Project Foundation (HPF), Vicenza, Italy, for excellent organizing and secretarial assistance.

This work was supported by the Hematology Project Foundation (HPF), Vicenza, Italy. HPF supported the IWG meetings by providing both logistic and financial support, which covered the cost of rooms, audiovisual equipment, and meals. (HPF receives limited unrestricted grants to support educational programs by pharmaceutical industries including Amgen Europe and GlaxoSmithKline Europe.)

Contribution: F.R. coordinated the project, chaired the meetings, and wrote the manuscript. M.M., T.G., and R.S. wrote the manuscript. M.R. acted as scientific secretary for the meetings and wrote the manuscript. J.B.B., D.B.C., A.G., and R.J.K. contributed to specific parts of the manuscript. V.B., N.C., B.G., P.I., M.K., T.K., H.L., M.G.M., A.N., I.P., and A.T. were active members of the International Working Group. All reviewed the final version of the manuscript and gave their approval.

Conflict-of-interest disclosure: F.R. is a member of advisory boards and speaker for Amgen, GlaxoSmithKline, Eisai, and LFB. M.M. is a member of advisory boards for Amgen and GlaxoSmithKline and received research funding from Roche. He participated as a speaker for symposia for Amgen, GlaxoSmithKline, Roche, and Bristol-Myers Squibb. T.G. is a consultant for Amgen, Symphogen, and GlaxoSmithKline. M.R. received honoraria from Amgen Italy and GlaxoSmithKline Italy for speaking engagements. J.B.B. received clinical research support from Amgen, Cangene, GlaxoSmithKline, Genzyme, IgG of America, Immunomedics, Ligand, Eisai, Shionogi, and Sysmex. His family owns stock in Amgen and GlaxoSmithKline. He has participated on advisory boards for Amgen, GlaxoSmithKline, Ligand, Shionogi, Symphogen, and Eisai. He also had a 1-day consult with Portola. D.B.C. is a member of medical advisory boards for Amgen, GlaxoSmithKline, and Eisai. N.C. received honoraria from Amgen and GlaxoSmithKline for speaking at educational meetings and consultancy work. B.G. is a member of advisory boards for Amgen, GlaxoSmithKline, LFB, and Roche. He received research funding from Roche. P.I. received institutional unrestricted support from Amgen and GlaxoSmithKline. M.K. is member of advisory boards for Amgen and GlaxoSmithKline and received research funding from Roche. T.K. received unrestricted grants from Amgen and GlaxoSmithKline. H.L. is a consultant for Bristol-Myers Squibb, Eisai, Janssen (Johnson & Johnson), and Sanofi and received research support from Bristol-Myers Squibb, Eisai, GlaxoSmithKline, and Sanofi. M.G.M. is a consultant for Amgen and GlaxoSmithKline. A.N. acted as consultant for Amgen, GlaxoSmithKline, and Pangenetics. He participated in advisory boards and/or as a speaker at medical education events supported by Amgen, Baxter, Celgene, GlaxoSmithKline, and Roche and received research support from Amgen, Eisai, Genentech, and GlaxoSmithKline. I.P. is a member of advisory boards and speaker for Amgen and GlaxoSmithKline and received an unrestricted research grant from GlaxoSmithKline. R.S. has served as a consultant for Amgen, GlaxoSmithKline, and Suppremol and has participated on advisory boards and/or as a speaker at medical education events supported by Amgen, GlaxoSmithKline, Nycomed, Symphogen, Novo, Bayer, and Baxter. The remaining authors declare no competing financial interest.

Correspondence: Francesco Rodeghiero, Department of Cell Therapy and Hematology, San Bortolo Hospital, Viale Rodolfi 37, 36100 Vicenza, Italy; e-mail: rodeghiero@hemato.ven.it.